Benign Prostatic Hyperplasia (BPH), also called Benign Prostatic Hypertrophy, is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is surgery (Lepor, H. Urol. Clinics North Amer., 17, 651 (1990)). Over 400,000 prostatectomies are performed annually (data from 1986). A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
xcex1-Adrenergic receptors are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many xcex1-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). xcex1-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists), which act to block the effects of norepinephrine. Many of these drugs are effective but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
During the past 15 years a more precise understanding of xcex1-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one xcex1-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two xcex1-adrenergic receptors--xcex11 and xcex12--existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six xcex1-adrenergic receptors which exist throughout the central and peripheral nervous systems: xcex11A, xcex11B, xcex11C, xcex12A, xcex12B and xcex12C (Bylund, D. B., FASEB J., 6, 832 (1992)). It is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, many xcex1-adrenergic drugs that were developed before 1992 are not selective for any particular xcex1-adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor xcex1-adrenergic receptor selectivity.
Since the mid 1970""s, nonselective xcex1-antagonists have been prescribed to treat BPH. In 1976, M. Caine, et al. (Brit. J. Urol., 48, 255 (1976)), reported that the nonselective xcex1-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with xcex1-receptors located on the prostate. However, this drug also produces significant side effects which severely limit its use in treating patients on a chronic basis. More recently, the xcex1-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH. However, these drugs also produce untoward side effects. The most recently approved drug Proscar (Merck) prescribed for BPH is not an xcex1-adrenergic antagonist, but rather acts by blocking 5-xcex1-reductase. While Proscar is able to relieve symptoms, it is effective in only 30% of all patients, and requires a period of up to 6 months to show results.
From binding studies using cloned rat xcex11A, hamster xcex11B, and bovine xcex11C receptors, and functional studies of antagonism in vitro using human prostrate, I. Marshall, et al., concluded that the receptor mediating contraction of the human prostrate is of the xcex11C subtype (Marshall, I., et al., Brit. Pharmacol. Soc., (1992)).
Furthermore, using cloned human receptors the binding characteristics of the known BPH drugs to various receptor subtypes have been determined, as described more fully hereinafter. Based upon such binding information and additional data, it has been observed that the side effects which occur with the drugs prazosin and terazosin may be due to their poor selectivity for specific xcex1-adrenergic receptors. In contrast, indoramin is a drug which is slightly selective for the human xcex11C receptor relative to the other human xcex1-adrenergic receptors, but it also interacts at human histamine H1 receptors. This compound produces untoward side effects which may be attributed to its activity at such H1 receptors.
It would be desirable to provide methods and compounds which allow the treatment of BPH but which avoid the production of side effects observed for all currently used medications.
From the binding information described hereinafter, it has unexpectedly been discovered that compounds which are specific for an xcex11C adrenergic receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compounds bind to an xcex11A adrenergic receptor, a human xcex11B adrenergic receptor, and a human histamine H1 receptor, and (b) bind to an xcex12 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compounds bind to such xcex11C adrenergic receptor are effective for the treatment of BPH.
Furthermore, we have characterized several antagonists selective for the xcex11C adrenergic receptor using a rat orthostatic hypotension model to ascertain the vascular effects of drugs which may be indicative of their ability to produce dizziness in patients, and observed that while nonselective alpha 1 antagonists produce significant effects on orthostatic hypotension, selective alpha 1c antagonists do not produce significant effects.